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Pharmacol Res. 2015 Jul;97:7-15. doi: 10.1016/j.phrs.2015.04.001. Epub 2015 Apr 14.

Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive.

Author information

1
Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego, 30, Genova 16163, Italy.
2
Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA. Electronic address: kmwagner@ucdavis.edu.
3
Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
4
Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine 92697-4621, USA.

Abstract

We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators--fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively--which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.

KEYWORDS:

Acute and chronic pain; Anti-nociception; Epoxidized fatty acid (EpFA); Fatty acid amide hydrolase; Fatty acid ethanolamide (FAE); Soluble epoxide hydrolase

PMID:
25882247
PMCID:
PMC4464910
DOI:
10.1016/j.phrs.2015.04.001
[Indexed for MEDLINE]
Free PMC Article

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